PROJECT SUMMARY Relapse to drug abuse is the single greatest challenge in addiction treatment. Relapse can occur even after prolonged abstinence and is often preceded by robust drug craving precipitated by exposure to drug-paired stimuli and environments. However, presently little is known about the neural substrates that mediate drug craving and relapse. The long-term goal of this project is to characterize the corticostriatal neural network dynamics that accompany cocaine craving and relapse with an emphasis on their modulation by the endocannabinoid system. The current aims of this proposal are to examine the longitudinal development of potentiated corticostriatal circuit representations of cocaine-paired stimuli and their necessity in promoting cocaine-seeking behavior in rats; to assess whether environmental enrichment (wheel running) diminishes recruitment of mPFC-NAc network encoding of cocaine-paired stimuli as well as cocaine seeking; and, finally, to investigate whether augmenting accumbal activity-dependent, synapse-specific endocannabinoid levels attenuates heightened mPFC-NAc network dynamics and cocaine-seeking behavior. It is hypothesized that (1) cocaine-motivated behavior during extended forced abstinence from cocaine self-administration will be mediated by heightened recruitment of mPFC-NAc network activity and (2) exposure to environmental enrichment during forced abstinence as well as pharmacological enhancement of accumbal endocannabinoid neurotransmission will attenuate mPFC-NAc network encoding of cocaine-paired stimuli and cocaine seeking. These experiments will employ a sophisticated rat model of drug craving and relapse, state-of-the-art in vivo multi-unit electrophysiological recordings, chemogenetic technologies, and novel pharmacological agents to examine these questions in behaving animals. The proposed experiments aim to increase our understanding of the neuronal mechanisms that mediate drug craving and may improve our potential to predict relapse vulnerability and identify effective pharmacological and behavioral therapies.